Bar-Ilan team shows one DNA letter outside any gene can switch a mouse's sex

Researchers at Bar-Ilan University reported on 9 April 2026 in Nature Communications that changing a single letter of DNA, in a stretch that contains no gene at all, was enough to make genetically female mice grow testes and male anatomy. The study was led by doctoral student Elisheva Abberbock in the laboratory of Dr. Nitzan Gonen at the Mina and Everard Goodman Faculty of Life Sciences, with collaborators including Dr. Ariel Afek of the Weizmann Institute and Dr. Francis Poulat of the University of Montpellier.

The work centres on Enh13, an enhancer: a piece of so-called non-coding DNA that acts like a dimmer switch for a nearby gene. Enh13 controls Sox9, a gene that must be turned on for testes to form. Using CRISPR gene editing, the team made tiny changes to Enh13 in mice with two X chromosomes, including a one-letter insertion and a three-letter deletion. In each case Sox9 switched on when it should have stayed off, and the XX mice developed as males. In 2024 Gonen's group had shown that other small changes in the same region did the reverse, causing XY mice to develop as females. Together the studies show that Enh13 both drives male development and must be actively held down for ovaries to form. Gonen noted that the change involved one DNA letter out of about 2.8 billion.

The findings matter for people. Differences of sex development, in which chromosomes, gonads or anatomy do not line up in the typical way, occur in roughly one in 4,000 births. More than half of these cases have no genetic explanation even after the genes themselves are sequenced, leaving families without answers about cause, health risks or fertility. The Bar-Ilan results suggest that some of the missing explanations lie in regulatory regions like Enh13. Katie Ayers of the Murdoch Children's Research Institute, who was not involved, told The Times of Israel that checking such regions in patients could lead to more diagnoses. Gonen called Enh13 the tip of the iceberg, and the lab plans to test more of these switches.